The following includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art.
In humans and other mammals, wound injury triggers an organized complex cascade of cellular and biochemical events that will in most cases result in a healed wound. An ideally healed wound is one that restores normal anatomical structure, function, and appearance at the cellular, tissue, organ, and organism levels. Wound healing, whether resulting from trauma, microbes, or foreign materials, proceeds via a complex process encompassing a number of overlapping phases, including inflammation, epithelialization, angiogenesis, and matrix deposition. Normally, these processes lead to a mature wound and a certain degree of scar formation. Although inflammation and repair mostly occur along a prescribed course, the sensitivity of the process is dependent on the balance of a variety of wound healing modulating factors, including, for example, a complex network of regulatory cytokines and growth factors.
Gap junctions are cell membrane structures that facilitate direct cell-cell communication. A gap junction channel is formed of two connexons (hemichannels), each composed of six connexin subunits. Each hexameric connexon docks with a connexon in the opposing membrane to form a single gap junction. Gap junction channels are reported to be found throughout the body.
Connexins are a family of proteins, commonly named according to their molecular weight or classified on a phylogenetic basis into alpha, beta, and gamma subclasses. At least 20 human and 19 murine isoforms have been identified. Different tissues and cell types are reported to have characteristic patterns of connexin protein expression.
Antisense technology has been reported for the modulation of the expression for genes implicated in viral, fungal, and metabolic diseases. See, e.g., U.S. Pat. Nos. 5,166,195, 5,004,810. Antisense technology has also been developed to modulate connexins and treat wounds. See, e.g., U.S. Pat. Nos. 7,098,190, 7,879,811, 7,902,164, 7,919,474, 8,034,789, 8,059,486, 8,063,023, 8,181,580, and 8,314,074. Peptide inhibitors of gap junctions and hemichannels have also been reported. See, e.g., WO2006/134494, published U.S. patent application publication no. 20100279921.
Despite advances in the understanding of the principles underlying the wound healing process, there remains a significant unmet need in suitable therapeutic options for chronic wound care. These inventions address this continuing need.